My research group is interested in macromolecular structure and dynamics and the relationship of these to biological function. The primary tools we use involve a range of computer modeling methods, including molecular graphics and molecular mechanics (Monte Carlo, molecular dynamics, and so on). Our models cover all sizes of biological molecules and molecular assemblies, so the models are sometimes done in all-atom detail, and sometimes at lower resolution (often called "reduced representations", or "coarse-grain modeling"). We have experimental collaborations on all projects, and students in my lab are strongly encouraged to develop research projects involving both experimental and modeling components.
Computational structural biology, originally developed to assist in the x-ray crystallographic determination of macromolecular structures, has evolved into a sophisticated independent method for investigating structure-function relationships in biomolecules. Many scientists now regard computational science as a third branch of science, complementing traditional experimental and theoretical approaches.
Structure-function relationships in the ribosome: The ribosome is responsible for translating the genetic message contained in mRNA into the correct protein sequence, and many antibiotics attack bacterial ribosomes. The structures of the ribosomal large and small subunits have recently been determined by x-ray crystallography, providing a snapshot of the structure at reasonably high resolution. Cryo-electron microscopic studies of complexes of mRNA, tRNA, and various cofactors have captured the ribosome at several points in the translational cycle, but only at low resolution. We and our collaborators are combining the data from these and other experiments into detailed models with the aim of determining the structural, thermodynamic, and kinetic basis of translational initiation, fidelity, elongation and termination. We are also investigating evolutionary issues related to the structure of the ribosome and tRNAs.
Viral assembly: Understanding the mechanisms whereby viruses package their nucleic acids should offer new opportunities for drug design. We have two major efforts underway in this area. First, we are developing models for investigating structural and thermodynamic issues related to the packaging of double-helical DNA into bacteriophage capsids. Second, we are investigating the interplay between RNA secondary structure and RNA-protein binding in the assembly of small RNA nodaviruses. The models of both DNA viruses and RNA viruses are based on available data from x-ray diffraction and cryo-electron microscopy, and they are being evaluated against results from a variety of other kinds of experiments.
Lipoproteins and atherosclerosis: Low density lipoproteins (LDLs) deliver cholesterol to peripheral tissues, while high density lipoproteins (HDLs) are responsible for clearing cholesterol from peripheral tissues and delivering it to the liver, so the balance between the levels of LDLs and HDLs is a critical factor for the risk of coronary artery disease. We are collaborating with several experimentalists to incorporate all available information into detailed atomic models for HDLs and LDLs, in an effort to understand structure-function relationships in these particles.